Structural studies of nucleoside analog and feedback inhibitor binding to Drosophila melanogaster multisubstrate deoxyribonucleoside kinase

Niels Egil Mikkelsen, Birgitte Munch-Petersen, Hans Eklund

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

    Abstract

    The Drosophila Melanogaster multisubstrate deoxyribonucleoside kinase (dNK) has a high turnover rate and a wide substrate range that makes it a very good candidate for gene therapy. This concept is based on introducing a suicide gene into malignant cells in order to activate a pro-drug that eventually may kill the cell. To be able to optimize the function of dNK, it is vital to have structural information of dNK complexes. Here we present crystal structures of dNK complexed with four different nucleoside analogs floxuridine (5FdU), brivudine (BVDU), zidovudine (AZT) and zalcitabine (ddC) and relate them to the binding of substrate and feedback inhibitors. dCTP and dGTP binds similarly as the feedback inhibitor dTTP with the base in the substrate site. All investigated nucleoside analogs bind similarly as the pyrimidine substrates with many interactions in common. In contrast, the base of dGTP adopts a syn-conformation to adapt to the available space of the active site.
    OriginalsprogEngelsk
    TidsskriftFEBS Journal
    Vol/bind275
    Udgave nummer9
    Sider (fra-til)2151-2160
    Antal sider10
    ISSN1742-464X
    DOI
    StatusUdgivet - 2008

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